We intend to suggest ways of designing penicillin and cephalosporin antibiotics which will be less susceptible to breakdown by beta-lactamase enzyme defenses of resistant bacteria, now that we have undertaken the X-ray structure analysis of an R-factor penicillinase in E. coli (J. Mol. Biol. 104, 865, 1976). We are confident that a complete X-ray diffraction analysis of a penicillinase/penicillin complex will show how various penicillins are bound to the active site on penicillinase prior to and during breakdown to inactive penicilloic acids. These stereochemical results will allow a precise determination of how organic chemists might change penicillin, by design rather than by trial-and-error, to prevent its destruction by the enzyme. The chemical modification must not alter the antibiotic's effectiveness, probably due to its being mistaken for one of the cell wall precursors. We have therefore looked for structural similarities between penicillin and N-acetylmuramic acid (Acta Cryst. B30, 365, 1974) and will examine L-lysyl-D-alanyl-D-alanine. The conformational analysis so far supports the hypothesis that penicillin is antibiotic at the transpeptidation stage of cell wall synthesis. Firm proof of mechanism can come from an X-ray structure analysis of a receptor/penicillin complex, for we have just crystallized a D-alanyl-carbosypeptidase-transpeptidase from Streptomyces R61 which is believed to be the pencillin target enzyme. An X-ray analysis of the penicillin-receptor interaction will reveal which parts of penicillin are necessary for recognition by receptor and which parts can be modified to prevent recognition by cell-protecting penicillinases.